Clinical- pathological correlative studies have demonstrated that the symptoms and signs of many age- associated neurological diseases, including disorders of motor neurons, are the result of dysfunction/death of specific populations of nerve cells in the central and peripheral nervous systems (CNS/PNS). For example, individuals with amyotrophic lateral sclerosis (ALS) suffer weakness and spasticity caused by lesions of lower and upper motor neurons, respectively, whereas patients with multiple system atrophy (MSA) develop, among other signs, impotence and incontinence, both of which are caused by lesions of Onufrowicz's (Onuf's) nucleus. This proposal, outlines investigations of several animal models that are characterized by degeneration of different subsets of motor neurons. Investigations of these models are designed to clarify some of the mechanisms of neuronal degeneration and to test neurotrophic therapies intended to influence the function/viability of these subsets of cells that are vulnerable in human diseases. Neurotrophins and neural cytokines act upon specific populations of cells (i.e., those bearing receptors for these factors), and the first part of this proposal describes studies of the basic biology of trophic factors. For these investigations, in situ hybridization will be utilized to demonstrate transcripts of trophic factors and receptors and retrograde transport techniques to visualize potentially responsive neurons. The character of transported neurotrophins/receptors will be examined. Second, on-going investigations designed to characterize several models associated with dysfunction/death of motor neurons are described including: axotomy-induced retrograde degeneration paradigms of somatic motor neurons, neurons of Onuf's nucleus, and corticospinal neurons; hereditary canine spaniel muscular atrophy, presently the best available model of motor neuron disease; and murine motor neuron disease (Mnd), an autosomal dominant disorder in mice. Using these model systems, the ability of trophic factors to ameliorate behavioral abnormalities and degenerative processes that occur in neural circuits damaged by different types of diseases will be tested. The demonstration that specific factors influence the viability/functions of vulnerable neuronal systems in these settings will allow the design of biological therapies to treat some of these neurological disorders in humans.